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Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease‐associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype‐specific morphological features. Here, we aimed at enhancing the understanding of these subtype‐specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot–Marie‐Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non‐myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle. [ABSTRACT FROM AUTHOR]

It is always a challenge to acquire a clear picture of the pathological processes and changes in any disease. For this purpose, it is advantageous to directly examine the affected organ. Nerve biopsy has been a method of choice for decades to classify peripheral neuropathies and to find clues to uncover their etiology. The histologic examination of the peripheral nerve provides information on axonal or myelin pathology as well as on the surrounding connective tissue and vascularization of the nerve. Minimal requirements of the workup include paraffin histology as well as resin semithin section histology. Cryostat sections, teased fiber preparations and electron microscopy are potentially useful in a subset of cases. Here we describe our standard procedures for the workup of the tissue sample and provide examples of diagnostically relevant findings. [ABSTRACT FROM AUTHOR]

Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative. [ABSTRACT FROM AUTHOR]

Aim Upon denervation, skeletal muscle fibres initiate complex changes in gene expression. Many of these genes are involved in muscle fibre remodelling and atrophy. Amyotrophic lateral sclerosis ( ALS) leads to progressive neurodegeneration and neurogenic muscular atrophy (NMA). Disturbed calcium homeostasis and misfolded protein aggregation both in motor neurones and muscle fibres are key elements of ALS pathogenesis that are mutually interdependent. Therefore, we hypothesized that the calcium sensor STIM1 might be abnormally modified and involved in muscle fibre degeneration in ALS and other types of NMA. Methods We examined ALS and NMA patient biopsy and autopsy tissue and tissue from G93 A SOD1 mice by immunohistochemistry and immunoblotting. Results In normal human and mouse muscle STIM1 was found to be differentially expressed in muscle fibres of different types and to concentrate at neuromuscular junctions, compatible with its known role in calcium sensing. Denervated muscle fibres of sALS and NMA cases and SOD1 mice showed diffusely increased STIM1 immunoreactivity along with ubiquitinated material. In addition, distinct focal accumulations of STIM1 were observed in target structures within denervated fibres of sALS and other NMA as well as SOD1 mouse muscles. Large STIM1-immunoreactive structures were found in ALS-8 patient muscle harbouring the P56 S mutation in the ER protein VAPB. Conclusion These findings suggest that STIM1 is involved in several ways in the reaction of muscle fibres to denervation, probably reflecting alterations in calcium homeostasis in denervated muscle fibres. [ABSTRACT FROM AUTHOR]

In this study we describe a case of a term infant with the neurological variant of Waardenburg syndrome type 4 (i.e., PCWH = peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, as defined in OMIM #609136) due to a novel heterozygous base exchange (c.671C>G) in exon 4 of SOX10. Magnetic resonance imaging suggested central myelin deficiency with cerebral and cerebellar hypoplasia. Hirschsprung disease was confirmed by rectal biopsy. Sural nerve biopsy revealed hypoplasia due to amyelination (with the exception of a single, small myelinated fiber) and severe reduction in the number of axons. Muscle Nerve, 2012 [ABSTRACT FROM AUTHOR]

Despite numerous clinical and experimental studies on botulinum toxin type A (BoNT/A), long-term alterations of muscle texture and fine structure following BoNT/A treatment have thus far not been studied in normal human skeletal muscle. After obtaining institutional review board approval, we performed a prospective, placebo-controlled, double-blinded follow-up study on two healthy adults using magnetic resonance imaging (MRI) and muscle biopsy to visualize long-term alterations after a single BoNT/A injection into the lateral head of the gastrocnemius muscle. MRI disclosed a high-signal-intensity pattern in short tau inversion recovery sequences, and a reduction of the cross-sectional area in the BoNT/A-injected, but not in the saline-injected contralateral control muscle (at 6 to 9 months in volunteer A: 73%, in B: 62%; at 12 months in A: 88%, and in B: 78%). Enzyme histochemistry, 12 months after injection, confirmed neurogenic atrophy of muscle fibers only in the BoNT/A-injected muscle. Electron microscopy revealed additional degenerative changes at the neuromuscular junction. The data confirm that MRI is a suitable tool to monitor the long-term effect of BoNT/A on skeletal muscle. Neurogenic muscle atrophy following a single BoNT/A injection should be taken into consideration when repeated BoNT/A injections into the same muscles are proposed. © 2009 Movement Disorder Society [ABSTRACT FROM AUTHOR]